title: Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease.
abstract: Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h)APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias.
authors.affiliation: Research Imaging Institute, San Antonio, TX, USA.
authors.forename: Ai-Ling
authors.initials: AL
authors.lastname: Lin
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Halloran
authors.forename: Raquel R
authors.initials: RR
authors.lastname: Burbank
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Hussong
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hart
authors.forename: Martin
authors.initials: M
authors.lastname: Javors
authors.forename: Yen-Yu Ian
authors.initials: YY
authors.lastname: Shih
authors.forename: Eric
authors.initials: E
authors.lastname: Muir
authors.forename: Rene
authors.initials: R
authors.lastname: Solano Fonseca
authors.forename: Randy
authors.initials: R
authors.lastname: Strong
authors.forename: Arlan G
authors.initials: AG
authors.lastname: Richardson
authors.forename: James D
authors.initials: JD
authors.lastname: Lechleiter
authors.forename: Peter T
authors.initials: PT
authors.lastname: Fox
authors.forename: Veronica
authors.initials: V
authors.lastname: Galvan
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D019335:Nitroarginine; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020123:Sirolimus